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Archive for the ‘Journal Club’ Category

Background
No where in medicine are the dreams for stem cells bigger than in treatment of diseases of the central nervous system. From neurodegenerative diseases to strokes to traumatic brain and spine injuries considerable work has been done. Specific attention being paid to autologous adult bone marrow stem cells which do not carry the risk of cancer, rejection and are readily available. Previous work has documented their ability to cross the blood brain barrier and to differentiate from BMSCs into microglia and neuralcells. In a recent edition of Neurosurgery a group from the Hokkaido University Graduate School of Medicine presented BMSC use in a rat model of TBI.

Design
The group induced “traumatic” lesions in 12 Sprague-Dawley rats by exposing a unilateral sensorimotor area with craniotomy and applying a freezing 7mm cylinder (cooled in liquid nitrogen) to the dura over the area causing an underlying lesion and significant post injury motor dysfunction.

Of the 12 rats 6 were then injected with an extimated 2 x 10^6 bone marrow stem cells in 200 microliters of saline through the ipsilateral internal carotid and 6 were injected similiarly with 200 microliters of saline. The injections occured 7 days post injury. The group derived the BMSC non-autologous bone marrow from the femurs of other Sprague-Dawley rats after death. These were labeled with PKH26 prior to implantation and with fluroscent cell markers for optical imaging.

The outcomes were functional recovery, in vivo optical imaging and histological examination after euthanasia.

Results
Optical imaging showed that in the ipsilateral side to the injury the injected BMSC left the vasculature and began engrafting into the damaged cortex as quickly as 1-3 hours after injection.

After death of the animals histological examination of the brain showed that the PKH26 labeled cells were primarily to be found in the damaged hemisphere and 22% showed NeuN and 18% showed GFAP implying that the BMSC were differentiating into neural elements.

Discussion
More importantly than showing functional recovery this paper’s biggest showing is a clinically, real world applicable method of stem cell administration, within a time frame that would be reasonable for clinicians and patient’s suffering traumatic brain injury.

Since Dawson demonstrated it in humans in 1946-1947 monitoring SSEPs during spinal surgery has become the norm rather than an exceptional available tool. It has spread from high risk deformity correction surgeries, such as scoliosis, to more mundane and typical procedures like fusions for trauma or degenerative disease.

Neuromonitoring during spinal surgery has become a huge industry and while population sized reports show a 50% decrease in neurological complications since monitoring came into wide use not all monitoring appears created equal and prospective studies trying to tease out the benefit of costly neuromonitoring have been inconclusive at best.

One of the newer additions to neuromonitoring is evoked EMG. And here is where the paper by Montes, et al out of the Hospital Ramon y Cajal in Madrid. In evoked EMG you stimulate something, usually the pedicle screw in spinal fusions, and see if the stimulation is conducted to neural tissue. The lower the level of stimulation required supposedly the closer the screw is to damaging a neural element (the spinal cord or a nerve, etc). One of the primary fears when placing these pedicle screws is placing the screw so that it is out of bone and in the spinal canal. It is a long held belief with EMG in neuromonitoring that stimulating the screw might give you evidence if you’ve broken through the bone medially. If the stimulation of the screw evoked a response at a low enough threshold then you removed the screw and replaced.

In an animal model the pediatric orthopedic practice in Spain wanted to see if there was a relationship between the stimulation needed to evoke a motor response in each screw and the integrity of the medial wall of the pedicle.

Design
Montes, et al used a porcine model. They placed a total of 18 viable screws in the thoracic columns of anesthetized pigs. The placed screws were measured and found 8mm from the spinal cord. With leads in the intercostal muscles the screws were stimulated in this position, 8mm from the cord with the medial pedicle bone intact, and the threshold at which stimulation of the muscle was achieved was recorded. The team then placed different materials in the canal, between the medial border of the pedicle (and the screw) and the dural sac. This organic material included bone, fat and muscle. With these interspersed tissues the EMG thresholds were again recorded. The team then removed the screws, took off some medial pedicle bone creating a “breach” and then replaced the screw so that it was 2mm from the spinal cord. EMG thresholds recorded the team then repeated the thresholds with fat, bone and muscle between the screw and the dural sac.

Results

The only association with the threshold for stimulation was the distance from the spinal cord.

The tissues between the screw made no difference. So whether the medial pedicle wall was intact or not had no effect at what stimulation there was a response in the muscle.

Discussion
It is true that other in vitro studies have shown that stimulation relates to the impedence from the screw to the neural elements (ie the tissues between the screw and the spinal cord) and the authors provide no answer for the discrepancy.

Taken alone these findings argue against somewhat the usefulness of evoked EMG in spinal fusion surgery in some ways. EMG cannot really give us a high sensitivty for breach of the pedicle cortex.

All EMG leaves us with is to have a very high tolerance for borderline thresholds on stimulation. The screws that should be replaced are those that have very, very low thresholds on EMG implying that they are touching or nearly touching neural elements. That in and of itself may still be of some use as its probably that proximity, more than the violation of the bone, that most puts patient at risk for injury (ie, even if there is no intervening tissue between the screw and the cord the fact that there’s some distance is safe in and of itself).

Background
It is common knowledge to avoid major teaching hospitals in July. Such is when new residents, fresh from medical school, begin as physicians. In some studies the month has been associated with more errors, including notably fatal medication errors. However, the effect continues to be questioned and debated. Even a short review of the surgical literature finds that a preponderence of studies show no worse outcomes with surgical procedures in July as compared to other months. The most notable of these studies is likely this large retrospective review of all Medicare patients undergoing CABG, CEA, AAA repair, colectomy, pnacreatectomy, esophagectomy or hip ORIF between 2003 and 2006. They found no increased mortality or reported morbidity in those three Julys as compared to the other 33 months of the study. Other studies looking just at patients undergoing CABG or patients undergoing emergent appendectomy back up those results.

McDonald, Robert J., Harry J. Cloft, and David F. Kallmes. “Impact of Admission Month and Hospital Teaching Status on Outcomes in Subarrachnoid Hemorrhage: Evidence against the July Effect.” Journal of Neurosurgery 116 (2012): 157-63.

Design
The study by a group out of the Mayo Clinic is a retrospective analysis of a huge proportion of all hospital admissions between 2001-2008 for non-traumatic subarachnoid hemorrhage. The study pulled all admissions with ICD codes associated with SAH from the National Inpatient Sample. This is an AHRQ national database contributed to by all hospitals in 44 states.

The admissions and their outcomes were studied with two linear regression models for both teaching and non-teaching hospitals. One looked solely at inpatient mortality. The other looked at “unfavorable” discharged; those patients with SAH being discharged to skill care.

Results
There were 52,879 admissions for non-traumatic SAH in the NIS database between 2001-2008. 36,914 were admitted to teaching hospitals and 15,965 were admitted to non-teaching hospitals. There was no monthly variation, in either teaching or non-teaching hospitals, in either model. The authors failed to find any evidence of a “July effect.”

Of note however, there was a discrepancy in outcomes in terms of hospital teaching status. The probability of in-hospital mortality for patients presenting to a teaching hospital with non-traumatic SAH was 11% lower than that or patients presenting to a non-teaching hospital. The probability of “unfavorable” discharge, likewise, was 12% lower.

Discussion

The results of this retrospective review of SAH hos -pital admissions within the 2001–2008 NIS failed to demonstrate significant month-to-month variation among outcomes including in-hospital deaths and/or discharges requiring skilled care. This pattern was observed in both teaching and nonteaching hospitals and suggests that a July effect is absent among SAH hospitalizations.

Also, for life threatening problems, such as subarachnoid hemorrhage, tertiary centers (more often than not teaching facilities) appear to be the place to go for care. At least in terms of outcome.

Background
God bless the British Medical Journal. Every Christmas they publish original research of humorous endeavor. Last year a couple of orthope(a)dic registrars and a consultant took a look at the stereotype that orthope(a)dic surgeons are meat heads; stronger than their physician counterparts and dumber as well. Here is the study, available in full.

Design
The study was a prospective non-randomized sampling which looked at 36 male orthopedic surgeons and 40 male anesthesiologists at three hospitals in the United Kingdom. It compared intelligence and dominant hand grip strength between the two groups.

Intelligence was measured using the iPhone app Mensa Brain Test, which poses questions taken from some actual Mensa, self administered, qualifying exam grading participants with a standard intelligence quotient.

Strength was measured using a dynamometer in the dominant hand.

Results

No surprise, the orthopedic surgeons were on the mean stronger than their matched anesthesiologists. The orthopedists generated 47.25 kg of force on mean in their dominant hand versus 43.83 kg for the anesthesiologists

The orthopedic surgeons also had a higher mean intelligence score as graded by the iPhone app, 105.19 versus 98.38 for the anesthesiologists.

Conclusion
While not a rigorous study, it is certainly cute. I think the authors sum up their conclusions better than I could:

The stereotypical image of male orthopaedic surgeons as strong but stupid is unjustified in comparison with their male anaesthetist counterparts. The comedic repertoire of the average anaesthetist needs to be revised in the light of these data. However, we would recommend caution in making fun of orthopaedic surgeons, as unwary anaesthetists may find themselves on the receiving end of a sharp and quick witted retort from their intellectually sharper friends or may be greeted with a crushing handshake at their next encounter.

Although the specifics of assessment and technique in fusion remain for debate spinal fusion for pain with spinal instability has become a generally accepted treatment

Surgery for fusion attempts to promote new boney growth between the unstable vertebral segments

Early last decade saw the rise in the clinical use of a naturally occurring cytokine, bone morphogenic protein-2, which serves to promote osteoblast differentiation and new bone formation in the body

Initial studies demonstrated great success, as compared to bone grafts alone, in promoting boney fusion between unstable segments when BMP was used during surgery

The Spine Journal June 2011 issue is dedicated to editorials and studies reviewing the growing evidence that BMP use has a number of risks that were underreported as adverse events in the initial studies which trumpted its use. Amongst these studies is a literature review by Carragee et al which criticizes the lack of reported adverse events in the initial industry sponsored BMP studies

Review of subsequent studies, unpublished data from the original studies submitted to the FDA leads the authors to conclude that BMP has a true adverse event rate of 10-50%. Newer studies may also associate the product with a cancer risk

Dr. Carragee’s group proposes that the financial ties of the authors of the original 13 studies may help explain the lack of reported complications with BMP

Conclusion
Spine surgery is facing a real scandal with BMP. The association with cancer and the implication that financial considerations influenced the studies which led to its approval as a device by the FDA and to its widespread use is a big enough story that it has crept out of the pages of Spine and into the mainstream media. Reuters, the AP have both reported on it, as have major papers like the San Francisco Chronicle and the New York Times and the Wall Street Journal.

Infuse and other BMP based products are likely rightly dead and recalls are in the future. As for what this plays into the long going debate about the association between researchers and industry remains to be seen. But this is a big deal.

I’m going to be less than reactionary here. I think severing the ties between academic medicine and industry is impossible without hurting the common good. This country is the leader in advancing medical science partly because of funding from industry. I think the oversight is going to have to come from the academic institutions themselves. That’s a tough thing and there are major obstacles to people policing their colleagues. I’m not sure exactly what form that might take. But certainly I don’t think the government is not in a position to police it all. And the alternative is severing all ties to industry funded research.

Background
The details of the medical malpractice environment have been studied in detail. The risks providers face of a claim, the risk factors for such, the results of such claims and the like. But previously the risks of claims, indemnity and such physicians of different specialties faced had not been published.

A new study by Dr. Chandra and his colleagues in the New England Journal of Medicine puts some numbers to the malpractice risk faced by various physician specialties.

Database of all closed claims filled between 1991 and 2005 from a large physician owned malpractice insurer

Insurer covered 40,916 unique physicians over that time period who self reported more than 200 medical specialties

Looked at all claims for each individual year for each specialty to calculate per annum risk

Broke claims into those with indemnity and without

For those claims with indemnity looked at mean and median payments for each specialty

Broke specialties into ‘high risk’ and ‘low risk’ and by Kaplan-Meier estimator gave estimations of cumulative lifetime risk of any claim and any claim leading to payment

Results
There was unsurprising considerable variability amongst specialties for risk for claim.

Procedure based specialties topped the risk of any claim with the annual risk for a neurosurgeon standing at 19.1%

There was more variability for mean and median indemnity payments. Perhaps not surprising specialties in which harm occured to younger patients had larger mean and median payments, even if the risk of claim was low. Pediatrics had the largest payments, topping more than $500,000.

There was also considerable variability, perhaps more difficult to explain, amongst specialties for the risk of a claim leading to an indemnity.

Critique

Although a large insurer, the study looked at data from but a single one

“Our model assumes that the probability of being sued was unrelated to the duration of coverage by the insurer”

“[Our model assumes] that the probability of being sued at a given age was independent of being sued at an earlier age (after adjustment for physician random effects)”

The mix of specialties may not be representative

Conclusion

It’s an interesting article and provides good data on risk by specialty. It also provides tangential insight into how physician behavior might be influenced by risk of suit. The author’s discussion of such might be the most interesting thing in the article in fact.

As in other surveys the risk of indemnity was relatively low. Nearly 80% of claims resulted in now payments in this sample. That has been one of the major points by opponents who find no basis for defensive medicine based on the malpractice ‘crisis’. However, as the authors speculate,

Although these annual rates of paid claims are low, the annual and career risks of any malpractice claim are high, suggesting that the risk of being sued alone may create a tangible fear among physicians.

The perceived threat of malpractice among physicians may boil down to three factors: the risk of a claim, the probability of a claim leading to a payment, and the size of payment. Although the frequency and average size of paid claims may not fully explain perceptions among physicians,1 one may speculate that the large number of claims that do not lead to payment may shape perceived malpractice risk. Physicians can insure against indemnity payments through malpractice insurance, but they cannot insure against the indirect costs of litigation, such as time, stress, added work, and reputational damage.

Background
The Corticosteroid Randomization After Significant Head injury (CRASH) trail was a huge international double blinded randomized trial which collected a huge cohort of patients suffering traumatic brain injuries with GCS less than 14 on presentation and presenting within 8 hours of injury and randomizing them to receiving a 48 hour course of methylprednisolone versus a placebo. The final results were published in The Lancet in 2005.

As if that was not enough the database collected for the study was the largest, most complete database of patients following head injury in the world. It included more than 10,000 patients from across the world and had a very high rate of follow up through 6 months. This database was used to create a prognostic model for outcome following head injury. Published in the British Medical Journal in 2008 the CRASH model has become one of more widely cited outcome prediction models in clinical practice when dealing with patients with head injury.

The original paper is available for free as full text on the BMJ website.

Design
This was a retrospective review of outcome of a large cohort of patients.

The database included 10,008 patients originally collected for the CRASH Trial. The database contained information on a large number of variables but the prognostic model focused on 9 initial variables: age, sex, etiology of the trauma, time on presentation, GCS on presentation, pupil reactivity on presentation, results of CT scan, whether the patient had a major extracranial injury, level of per capita income in the country where the injury occured.

They prognosed to two outcomes death within 14 days of injury or outcome at 6 months as measured by the Glasgow Outcome Score which they dicotomized into favorable outcomes (moderate disability or good recovery) and unfavorable outcomes (dead, vegetative state or severe disability).

They developed two models with the above variables: a basic model which excluded the findings on CT imaging and a CT model which included them.

Internally they validated the two models using bootstrap resampling. And then they externally validated the model using the 8000+ patients suffering head injury included in the independent International Mission for Prognosis And Clinical Trial (IMPACT) database. The original description of the IMPACT Trial is here on PubMed.

Results
All nine of the variables included in the final two models independently had strong associations with both outcomes (death at 14 days and poor outcome at 6 months). The table showing the odds ratios for each variable can be found here.

Regression of outcome of model including CT scan findings

After this internal validation they compared their model to outcomes observed in the IMPACT Trial blinded.

It showed good discrimination in the external validation with a C-score of 0.77 (essentially the area under the reciever operator curve). And for the basic model and the CT model in high income countries there was very good calibration by the Hosmer-Lemeshow test.

The authors have published a calculator with predictive outcomes based on the regression. The calculator gives odds for death at 14 days and poor outcomes at 6 months based on both models.

Critique
The sample size of this study is legitimate and one of the stronger points of it. The database appears well maintained and exceptionaly complete considering the number of patients and the challenges of coordinating data collection across continents. Looking at the demographics it appears relatively representative. As well the follow up to 6 months is a legitimate end point for the goals of the study and the sample included a great number of patients to that end point.

The outcomes measured to seem clinically relevant and were set prior to the models being designed. The variables included in the regressions as well have previously been validated at predicting outcomes in other smaller studies and are clinically readily available.

The study found no difference in outcomes based on treatment, including the randomization to steroids or placebo in the trial itself, which is an important consideration.

It is true the CT model in particular showed comparatively poor calibration for patients injured in lower income countries. Even there however the Hosmer-Lemeshow measure isn’t particularly off. The smaller sample size of patients with readily available CT imaging findings may in part explain such.

The major critiques otherwise of the study seem to be those available to be leveled at all published prognostic models. Generalization is a difficult thing especially to individual anecdotal scenarios. However for a study with in vivo data from patients seemingly encountered early following representative head injury and undergoing real world salvage attempts the model shows remarkable, if not perfect, calibration and discrimination.

Conclusion
The models developed from the CRASH trial are very likely the “best” available prognostic models for predicting outcome early after traumatic head injury. The calculator published by the authors appears a valid and useful tool for any health care provider encountering significant neurotrauma. A “better” prognostic model for the prediction of outcome early after head injury seems unlikely.